The present invention relates to biocompatible heart valves having increased resistance to calcification and thrombus formation. The heart valves of the present imvention include an effective amount of thrombus inhibiting and calcification inhibiting coating.
In particular, the heart valves of the present invention have incorporated therein an effective amount of applied coating to render the valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification. The subject invention also features a novel method for manufacturing heart valves having a thrombus resistant and calcification resistant coating.
The continuing advances in the design of heart valves prostheses and techniques for their implantation have produced impressive results in the length and quality of survival in patients who receive these devices. With the ever increasing effort to develop a more durable and compatible heart valve prosthesis, basic and clinical scientists have used a wide and varied number of techniques to determine the suitability of given valve materials for a given implant application. These techniques, aimed at determining the implant/host interaction, have generally been included under the term xe2x80x9cbiocompatibilityxe2x80x9d. Investigators commonly deal with biocompatibility in terms of whether the implant material or its degradation products, if any, initiate adverse tissue responses in the host or conversely whether deleterious changes in the chemical, physical and/or mechanical properties of the implant material are caused by the host environment. The vast majority of fundamental studies of biocompatibility involve animal models. The ultimate test for biocompatibility of a polymer, device or prosthesis, is human implantation.
Prosthetic heart valves in clinical use today are of two varieties, mechanical and tissue. Mechanical heart valves are very durable, but their use is complicated by thromboembolism, hemorrhage, and hemolysis. Tissue valves require no chronic anticoagulation of the patient but often fail due to calcification and tissue tearing. Potential alternative materials that are sufficiently durable and blood compatible for use in a prosthetic heart valve device include non-glutaraldehyde fixed bovine pericardial tissue, which has been observed in the ovine mitral model to calcify less than does glutaraldehyde fixed tissue, and synthetic polymers such as polyurethanes, which have been reported in many different models to also calcify less than does glutaraldehyde fixed bovine pericardial tissue.
This invention relates generally to biocompatible heart valves which are resistant to in vivo calcification, and more particularly, to calcification-resistant and thrombus resistant heart valves comprising synthetic polymers or materials of natural origin, such as bovine pericardium, porcine heart valves or homografts, having incorporated therein an effective amount of a coating to impart resistance to calcification and impart resistance to thrombus formation.
The precise mechanism for pathological calcification of cardiovascular tissue is not well understood. Generally, the term xe2x80x9cpathologic calcificationxe2x80x9d refers to the deposition of calcium phosphate mineral salts in association with a disease process. See Schoen et. al, xe2x80x9cBiomaterial-associated calcification: Pathology, mechanisms, and strategies for preventionxe2x80x9d, J. Biomed. Mater. Res.: Applied Biomaterials, Vol. 22 A1, 11-36 (1988), incorporated herein by reference. Calcification may be due to host factors, implant factors, and extraneous factors such as mechanical stress. There is some evidence to suggest that calcium deposits are related to devitalized cells, especially membrane cells, where the calcium pump (Ca+2-Mg+2-ATPase) responsible for maintaining low intracellular calcium levels is weakened or no longer functioning. Calcification has been observed to begin with an accumulation of calcium and phosphorous, present as hydroxyapatite, which develops into nodules which can eventually lead to a valvular failure.
The location of calcific sites on a heart valve prothesis may be intrinsic, i.e., within the boundaries of the biomaterials of the prosthesis, or extrinsic, i.e., outside of the biomaterials, perhaps attached to the valve prosthesis, e.g., within thrombus or other pseudointima. Extrinsic calcification itself rarely causes failure of bioprosthetic valves; the predominant calcific deposits responsible for bioprostietic valve failure are intrinsic. With polymer valves it is believed that both intrinsic and extrinsic calcification must be controlled. Therefore a biocompatible heart valve prosthesis is needed that is resistant not only to thrombus formation, but also to calcification, particularly intrinsic calcification.
In its broad embodiment, the present invention is directed to a biocompatible heart valve having incorporated therein an effective amount of applied coating to render said heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification.
The instant invention is also directed to a bioprosthetic heart valve comprising: a stent defining a blood flow path; and a plurality of leaflets, each of said leaflets having incorporated therein an effective amount of a photochemically applied coating to render said heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification.
In another aspect, the present invention relates to a polymeric bioprosthetic heart valve comprising: a stent defining a blood flow path; and a plurality of polymeric based leaflets, each of said leaflets having incorporated therein an effective amount of a applied coating to render said heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification.
The instant invention is also directed to a bioprosthetic heart valve comprising: a stent defining a blood flow path; and a plurality of silicone rubber leaflets, each of said leaflets having incorporated therein an effective amount of a photochemically applied coating to render said heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification.
The invention also provides a bioprosthetic heart valve comprising: a stent defining a blood flow path; and a plurality of phosphonate modified polyetherurethane leaflets, each of said leaflets further having incorporated therein an effective amount of a photochemically applied coating to render said heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic calcification.
The coatings that are effective to achieve resistance to in vivo thrombus formation and resistance to in vivo pathologic calcification are derived from photochemically activated precursors. Generally the coatings are derived from precursors of the general formula:
X-Y-Z
wherein X is a photochemically reactive group capable upon activation of bonding to the surface of the heart valve; Y represents nothing or a relatively inert, noninterfering skeletal moiety joining group X and is resistant to cleavage in aqueous physiological fluids and Z represents a functionally active moiety or biocompatible agent. The noninterfering skeletal moiety of Y may include an alkyl chain (C1-C10) or PEO (polyethylene oxide) (MW=200-1450).
The biocompatible heart valves of the present invention can be made of a biomaterial selected from the group consisting of natural tissue and biocompatible synthetic polymer. The natural tissue biomaterial is typically selected from the group consisting of bovine pericardium tissue and porcine tissue while the synthetic polymeric material is an organic synthetic material selected from the group consisting of siloxane polymers, polydimethylsiloxanes, silicone rubbers, polyurethane, polyether urethane, polyesterurethane, polyamide, polycarbonate, polyester, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, cellulose acetate, polymethylmethacrylate, and poly(ethylene/vinylacetate).
In the practice of the present invention, the valves are fabricated by dissolving the polymer in an appropriate solvent, and then a hard polymer stent is repeatedly dipped into the polymer solution and then dried. The coated stent is then placed over a leaflet mandrel, which is then dipped a predetermined number of times into the solution to provide valve leaflets of the desired thickness. The valves are typically of the multi-leaflet design. For surface modification, the valves are modified by dipping in the appropriate chemical solution or spraying appropriate chemical solution, and then exposed to light of a given wavelength so as to deposit the coating. The coating process can be repeated several times as desired.
The biocompatible polymer valves of the present invention are typically of the tri-leaflet design, which are similar to the design of bioprosthetic valves used clinically. To minimize residual stresses, a hard polymer stent is repeatedly dipped into a polymer solution, and the cast polymer is then heat cured. The valves are surface modified to improve the blood compatibility of the base polymer.
The present invention further provides a method for reducing calcification and thrombus formation in bioprosthetic heart valves after implantation in an animal comprising: coating, prior to implantation, said heart valves including its leaflets with a coating derived from a compound of the formula
X-Y-Z
wherein X is a photochemically reactive group capable upon activation of bonding to the surface of the heart valve; Y represents nothing or a relatively inert, noninterfering skeletal moiety joining group X and is resistant to cleavage in aqueous physiological fluids and Z represents a functionally active moiety or biocompatible agent. The noninterfering skeletal moiety of Y may include an alkyl chain (C1-C10) or PEO (MW=200-1450), said coating being in an effective amount to reduce calcification and thrombus formation after implantation.